PROJECT 2: The goals of this Project are to broaden our understanding of insulin resistance and specific features of the metabolic syndrome in the promotion and maintenance of pulmonary arterial hypertension (PAH) and to test the hypothesis that intervention on insulin resistance will ameliorate markers of pulmonary vascular disease. Data from our group shows a high prevalence of unrecognized glucose intolerance in human PAH. Our array data demonstrated that mitochondrial metabolic defects are closely tied to disease status. Moreover, data from our relevant mouse model shows that hyperglycemia and obesity predate development of pulmonary hypertension and correlate with histologic markers of oxidant stress that we can also measure in urine of human PAH patients. Hyperiipidemia and adipoklnes in animal models of pulmonary hypertension have also been shown to be important. Thus there is mounting translational evidence that metabolic defects, specifically insulin resistance, adipoklnes and hyperiipidemia, may promote PAH through oxidant stress and establishment of a proproliferative state. We hypothesize that insulin resistance with concomitant oxidative stress and mitochondrial dysfunction is a contributing factor to development and promotion of pulmonary vascular disease. Because of the proven safety of treatments for insulin resistance and diabetes and the high mortality of PAH, studies to test the effects of these drugs in human and animal models of PAH will potentially yield new, well-tolerated treatment strategies for the treatment of PAH. We propose three specific aims to test this hypothesis and to develop new treatments for PAH 1) Confirm the high prevalence of insulin resistance in human PAH using sensitive quantification techniques and correlate with markers of oxidant stress and proliferation 2) Demonstrate that insulin resistance predates development of PAH in humans and that insulin resistance worsens pulmonary vascular phenotype in our mouse model of PAH through oxidant stress and promotion of pulmonary vascular proliferation 3) Test the hypothesis that correction of insulin resistance using metformin in mouse and human PAH is safe and results in decreased lung oxidant stress and markers of lung cellular proliferation. The studies described here will allow us to determine in five years if therapies targeted at insulin resistance and metabolic defects in human PAH are likely to improve disease specific measures, e.g. invasive hemodynamics. We aim to propose a large-scale clinical trial in PAH incorporating these basic and clinical findings at the completion of year five to translate our data into meaningful improvements in PAH patient care. RELEVANCE (See instructions): Despite major advances in understanding PAH in recent decades, safe, effective and tolerable therapies remain elusive.The metabolic syndrome (central obesity, insulin resistance, systemic hypertension and hyperiipidemia) has been implicated in PAH. Treating the downstream consequences of metabolic syndrome in the pulmonary vasculature is a new approach to effective intervention against this highly mortal disease.